Method and device for generating microconvections

ABSTRACT

The invention relates to a method for generating a convective liquid motion in a fluidic microsystem. According to this method, a liquid in a microsystem is simultaneously exposed to an electrical field and a thermal gradient. The electrical field is generated by means of an electrode arrangement which is subjected to a time-variant voltage. In this way, a time variant electrical field is formed in the liquid volume. The thermal gradient is produced by means of at least one radiation absorber located in the compartment which is exposed to at least one external radiation field.

This application is a 371 National Stage Entry of PCT/EP01/12995 filedon Nov. 9, 2001.

BACKGROUND OF THE INVENTION

The invention concerns a method for the generation of a convectiveliquid motion in a fluidic microsystem, especially a method foreffecting mixing and turbulence in solutions or particulate suspensionsin a fluidic microsystem, which is subjected to the simultaneousformation of electrical and thermal field gradients, and the inventionfurther concerns a fluidic microsystem which is designed to enable theperformance of the said method.

Fluidic microsystems find many applications in biochemistry, medicineand biology, especially for analysis of dissolved substances andmanipulation of suspended particles. Due to the current miniaturizingand massive parallelization of the functioning processes in microsystemsor microchips, special advantages arise for the analysis and synthesisof many biological macromolecules which exist in high combinatorialnumbers (refer to G. H. W. Sanders et al., in Trends in AnalyticalChemistry, Vol 19/6, 2000, page 364 ff; W. Ehrfeld in Topics in CurrentChemistry, publisher, A. Manz et al., Vol. 194, Springer-Verlag, 1998,page 233 ff). Applications in the fluidic microsystems can be found infundamental research, notably DNA analysis or protein analysis, or evenin research of active substances in “combinatorial chemistry”.Additional applications arise in the analysis and the manipulation ofindividual biological cells or cell groups (see G. Fuhr et al., inTopics in Current Chemistry” publisher, A. Manz et al., Vol. 194,Springer-Verlag, 1998, page 83 ff).

A general problem of fluidic microsystems arises due to the smalldimensions of the compartments formed in the microchips, that is, thesize of channels, reservoirs and the like, which are measured in thesubmillimeter range. As a consequence, hydrodynamic liquid flows possesssmall Reynolds numbers and in turn, liquids move through fluidicMicrosystems in laminar flow. If in a microsystem any mixing of liquiddoes occur, then this is to be ascribed to diffusion of adjacent,laminar flows. In spite of the small dimensions of the microsystem, thediffusion of, for example, biological macromolecules, take placerelatively slowly, and on this account, the throughput of themicrosystem is severely limited.

An interest exists in achieving convective movement of liquids in amicrosystem (such as acquiring turbulence of a liquid or intermixing ofa plurality of liquids), which would be carried out with lesssluggishness and takes place predominately independent of thecharacteristics of the liquid and which would assure optical qualitiesserviceable for observation.

Various approaches are presently known for the introduction of liquidturbulence or the thorough mixing of liquids in Microsystems. The usageof mechanical mixers, as such are employed in the macroworld, is verymuch limited in Microsystems due to the intense shear and friction.Because of the agglomeration of macromolecules, mechanically movableparts of a microsystem are very prone to failure. Further, as describedby W. Ehrfeld, (see above) liquids do intermix by the separation offlows into partial channels, with a subsequent coalescing of the partialchannels to bring about a changed spatial arrangement. This technologyhas the disadvantage, that in the partial channels, once again, the flowis laminar. A fully and thorough mixing is not achieved. S. Shojidescribes in Topics in Current Chemistry 1988, (publisher A. Manz etal., Vol. 194, Springer-Verlag, 1998, page 167 ff) an intermixing ofliquids by inertial force, for example, a flow in lengthy, veryconvoluted channels. This technology, however, has the drawback, thatthe microsystem is handicapped by a complex apparatus. Beyond this, anintermixing of the liquids in the zig-zag channels can be achieved onlyby means of very high flow velocities (Reynolds number 2-100).

The generation of a convective liquid movement is also known, which isbased on the simultaneous buildup of electrical and thermal fieldgradients in fluidic Microsystems. FIG. 4 shows in a schematicillustration, a conventional system for convective liquid movement, ashas been disclosed by WO 00/37165. A compartment 10′ of a fluidicmicrosystem 100′ has, for example, a throughflow of particulatesuspension in the direction of arrow A. In the compartment 10′, it isintended that a turbulence in the liquid will occur. To this end, on thebottom 11′ is provided an electrode arrangement 20′, which is designedfor the establishment of electric field gradients transverse to thedirection A of flow. At the same time as the generation of theseelectrical field gradients, the liquid in the compartment 10′ is heated.This heating brings about a thermal gradient and results in a laminationof the of the liquid with differently arranged partial layerscorresponding to the thermal gradient. These partial layers, however,also possess different dielectric characteristics. By the action of theelectric field gradients, forces are brought to bear on the differentpartial layers, which effectively lead to a convective turbulence of theliquid. For the development of the thermal gradients, the proposal of WO00/37165 is to focus a laser beam in the arrow direction B through atransparent cover surface 13′. The liquid heats itself locally, as thedesired thermal gradient is formed. The focus point 40′ is located inthe liquid with a separating distance allowed from the bottom and theside surfaces, in accord with the double arrow.

Creating convective liquid movement as illustrated in FIG. 4 possessesseveral faults. This producing of localized heating of the liquid,presupposes a corresponding absorption of the radiation. For manysolutions, especially solutions or suspensions of interest in biologicalapplications, a severe limitation of employing a laser for the purposesof radiation exists. A further disadvantage is found in that it may bedesired to manipulate or optically detect suspended particles withlasers (optical cases). In some instances, this can lead to mutualinterference of the different radiations. Finally, the reproductivity ofconvection induced by field and radiation means is also limited, sincethe point of focus for the production of the local heating in the liquidcan only be repositioned again with reduced precision.

Thus the purpose of the invention is, to make available an improvedmethod for the generation of a convective motion in a liquid in afluidic microsystem, wherein the disadvantages of the conventionaltechnologies for achieving thorough mixing or turbulence in liquids areovercome. The method is to especially gain an expanded field ofapplication, in that the convective liquid motion is to be achievedindependently of the absorption properties or other characteristics ofthe liquid in a microsystem, and to be repeatable with a high degree ofreproducibility. The purpose of the invention further encompasses animproved microsystem to make this method operable.

SUMMARY OF THE INVENTION

A method for the generation of a convective liquid movement in a fluidicmicrosystem is described, wherein a liquid in the microsystem issimultaneously subjected to an electrical field and to a thermalgradient, whereby for the production of the electrical field, atime-variant voltage is applied to an electrode arrangement, so that, inthe liquid medium, a corresponding time-variant, electric field isformed and for the establishment of the thermal gradients at least oneradiation absorber, which is located in the compartment, is radiatedwith at least one external radiation field.

The basic concept of the invention, is to further develop theconventional technology for convective liquid motion by the simultaneousapplication of electric and thermal gradients in such a manner, that atleast one thermal gradient is produced in any compartment of interest ina microsystem, by means of simultaneous, time-variant electrical fieldsand by the radiation of affixed radiation absorbers, which are locatedin the said compartment. The locating of the radiation adsorber in themicrosystem has the advantage, that with external radiation, localheating results and a defined thermal gradient is established, which isindependent of the characteristics of the liquid with reproduciblegeometric characteristics and is produced without disturbance ofconcurrent optical measurements or manipulations in the saidmicrosystem.

In accord with the invention, the local heating in the microsystem iscreated by transmitting the radiation to the radiation absorbers. Theheating is generated by a radiation source, from which the energy istransmitted by direction and focusing, without physical contact, on theradiation absorber. There is no direct mechanical contact between theradiation absorber and the source of radiation. Much more, the radiationsource and the radiation absorber are set at a distance from oneanother. The heating of the radiation absorber is accomplished, forexample, by focusing at least one laser beam onto a radiation absorberor alternately by specific heating with high frequency radiation, suchas microwaves.

In accord with a preferred embodiment of the invention, a method forconvective liquid movement is designed to use infrared radiationabsorbers. The radiation absorbers are advantageously disposed on thewall surfaces of the compartments or they may be on electrodes in thecompartment. Particularly of advantage is the construction of at leastone electrode or electrode parts to serve as a radiation absorber. Forexample, the electrodes may be in partial layers and/or patterned on thesurface to serve as radiation absorbers. In this way, a direct heatingof the electrodes is enabled. The thermal gradients are automatically tobe found in the same zone of the liquid as are the electrical gradients.

The frequency of the time-variant electric fields is dependent upon theindividual application. This frequency represents, preferentially, theaverage, inverse dielectric relaxation time of the liquid and shows avalue, using an aqueous solution as an example, of about 1 kHz. For oilbased liquids this value can be 1 Hz or less.

An object of the invention is also a microsystem with at least onecompartment, which is conceived for the realization of the convectiveliquid motion in accord with the invention. The said compartment willexhibit at least one therein affixed radiation absorber. In accord withan advantageous embodiment example, a microsystem is constructed with atleast one external radiation source, with which the said at least one,fixed radiation absorber is heated. This combination possesses thespecial advantage of having a compact and universally applicable design.

The microsystem in accord with the invention also has the advantage of asimple construction. At optional locations in the fluidic microsystem,compartments with radiation absorbers can be provided for the convectivemotion of liquids by appropriate positioning of the electrodes for theestablishment of electrical fields and for affixing the radiationabsorbers.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

Further advantages and details of the invention become evident from thedescription accompanying the attached drawings. There is shown in:

FIG. 1 a schematic perspective view of a compartment of a fluidicmicrosystem which is designed for the execution of the invented method,

FIG. 2 a schematic top view of one embodiment of an inventedmicrosystem,

FIG. 3 a schematic top view of an additional embodiment of an inventedmicrosystem, and

FIG. 4 a schematic perspective view of a conventional microsystem, whichis designed for a convective motion of liquid in accord with the formerstate of the technology.

DETAILED DESCRIPTION OF THE INVENTION

The basic concept of the invention is initially explained with referenceto FIG. 1, in which the various advantageous achievements obtained fromradiation absorbers are illustrated. The implementation of the inventionis, however, not limited to these immediate, given achievements of thedifferent variants. Much more, in practice, it is possible to provide ina microsystem one or more of the radiation absorbers as depicted in FIG.1, or as called for by the application.

FIG. 1 shows a compartment 10 of a fluidic microsystem 100. Thecompartment 10 provides a optional section of a microsystem 100, whichis formed, as an example, by a channel, a reservoir, a confluence offlows, a diversion or another structure in the microsystem. Thecompartment 10 has, for example, a throughflow of a particulatesuspension in the direction of the arrow A and includes in its structureat least a bottom 11 and side surfaces 12. On the upper side, thecompartment 10 can remain open or it may be closed with a cover plate13. The cross section dimensions of the compartment lie typically in thesubmillimeter range. Further details of the fluidic microsystem 100,especially its function, its fabrication, and its structure are commonlyknown and on this account will not be further explained in detail here.

In compartment 10, it is intended that the liquid, flowing in thedirection of arrow A, or even if at a stillstand, be given a convectivemotion. To this end, there is to be found in compartment 10 an electrodearrangement 20 for the formation of a time-variant electrical field. Theelectrode arrangement 20 includes at least one free electrode, morepreferably however, at least two electrodes 21, 22, which are placed onone or more of the walls of the compartment 10. In FIG. 1, as anexample, 2 strip shaped electrodes 21, 22 are illustrated on the bottom11. Electrical supply lines for connection with a source of voltage(said source not shown) are provided in the conventional manner.

Further, in compartment 10 is affixed at least one radiation absorber30. A radiation absorber is an area which receives radiation, and isaffixed within the compartment with a defined spatial border. This canbe done by the introduction and the patterning of radiation absorbingmaterials in the compartment 10 and/or by the focusing of an externalfield of radiation in the arrow direction B onto fixed components in thesaid compartment 10, the components being, for instance, electrodes orwalls, etc. This means, that radiation absorbers can be created fromspecific wall areas, or from non-conductive extensions of theelectrodes. To serve as radiation absorbers, special absorber surfaces31 are provided on the various walls of the compartment 10, namely thebottom 11, the sidewalls, 12 or the cover 13. The absorber surfaces 31consist of an appropriately selected material, which has the greatestpossible absorption for the given external radiation field.

The size of the radiation absorber for an application is dependentfirst, upon the dimension of the compartment 10, second, on the shape ofthe external radiation field and third, on the capability of said fieldto achieve a focus. Further the size of the radiation absorber isadvantageously equal to half of the wave length of the chosen radiation.This size normally lies in the range of 0.5 to 25 μm.

Based on an advantageous and already realized variant, radiationabsorbers are formed from at least one electrode in its entirety (seereference number 32) or from a radiation absorbing, surface patterning33 applied onto at least one electrode (see electrode 21). If infraredlight is employed as an external radiation field, then the electrodes21, 22 consist, preferentially, of a “black body” material in theinfrared spectral range, such as titanium, tantalum or platinum. It isalso allowable that multilayer electrodes be employed, which consist oftitanium/platinum or chromium/gold. Alternative to this, it is possibleto install electrodes of a conductive, transparent material, such asITO, a conductive polymer, upon which the absorbing areas can becompletely covered or can be patterned, as may be seen illustrated inelectrode 21.

A turbulence and intermixing is achieved in compartment 10 bymechanisms, as these, in part, are known from conventional convectivemovement. By the establishment of electrical fields in inhomogeneousmedia, voltages are induced, and liquid movement occurs through theaction of these voltages. Because of the small geometric dimensions inthe microsystems, field strength gradients in the kV to MV range arecreated, which in turn produce turbulences on a microscale. For theinhomogenizing of the medium, i.e., the liquid in the compartment 10,this is carried out by the creation of localized thermal gradienteffects. Upon directed localized heating, the radiation absorberincreases in temperature. In the liquid, a temperature field forms witha gradient. Advantageously, the direct heating of the electrodes 21, 22can be done with infrared radiation, i.e., with an infrared laser. Thespecial advantage of this embodiment is found in that the areas of thegreatest field strength are definitely heated, and therewith becomedielectrically inhomogeneous, which leads to a particularly effectiveturbulence. The radiation absorbers located in accord with the inventionadditionally make it possible, that the turbulences can be locallylimited and the sluggishness of the system, because of the smallexpected volumes is especially small, this being some <0.1 s.

A further advantage arises in fluidic microsystems which emphasizedielectrophoretic manipulation of suspended particles. In cases in thisarea, the electrode arrangement 20 can be used simultaneously for theestablishment of the time-variant electrical field and for thedielectrophoretic manipulation of the particles (for instance,biological cells—see FIG. 3).

The coupling of the radiation field is done externally through at leastone transparent wall of the compartment 10 or by a light conductingoptical fiber. The coupling of the radiation field is accomplishedadvantageously in the direction (B), which deviates from the directionof flow (A) in the compartment. For the coupling through the wall, thenthe cover 13 or the bottom 11 must be of transparent material. This canbe plastic glass, or the like.

The radiation of the compartment 10, in accord with the type ofconstruction and absorption characteristics of the radiation absorbercan be effected by a beam which is spreading or is focused. Singlefocusing or multi-focusing can be employed. If the radiation is carriedout with a spreading beam, then more radiation absorbers can be heated.Corresponding to the geometric placement of the radiation absorber,there is created in the compartment 10 a defined pattern of turbulence.In the case of a focused radiation, then at least one focus point (seereference number 40) is directed at least one radiation absorber. Theradiation is carried out perpendicular to the bottom, the top, or theside surfaces of the compartment.

In order to assure that radiation directed at a radiation absorber bekept independent of the condition of the microsystem and thecharacteristics of the liquid in the compartment 10, advantageously, thewall is made of transparent material, on which are affixed one or moreradiation absorbers, such as electrodes. For instance, provision hasbeen made for the placement of electrodes of an infrared absorbingmaterial on a transparent bottom 11 or for the placement of multilayerelectrodes with an under-side layer of infrared absorbing material.

If entire partial areas of the compartment walls, because ofmanufacturing conditions, are made of an infrared absorbing material,then, the affixing of separate radiation absorbers can be dispensedwith. In this case, the invented method is then carried out, in that theexternal radiation field is focused on the wall of the compartment.

This focus point finds itself advantageously directly on the electrodesbordering on, or affixed to, the bottom 11 the cover 13.

The external radiation field can consist of a high frequency,electromagnetic radiation, which evokes inductive heating of theelectrode arrangement 20. Heating can also be provided by a thermalradiation of the electrode arrangement 20 from inset heating elements inthe wall or bottom 11 of the compartment 10.

FIG. 2 shows an embodiment of an invented microsystem 100 in schematictop view. Two channels 15, 16, which are bordered by side walls 12,have, respectively, differing liquids flowing through them and thesechannels open into common channel 17. The compartment 10, in which anintermix of the unlike liquids is to take place, is provided at thecommon junction of the channels 15, 16. The compartment 10 could, ifdesired, be located downstream at a distance from the channel 17, whichis also the junction of the channels 15, 16. The electrode arrangement20 includes two electrodes 21, 22 shown in dotted lines which are on thebottom 11 of the compartment 10, and two electrodes 23, 24 shown in fulllines, which are located on the top (not shown) of the compartmentdirectly opposite to the bottom electrodes. The radiation of thecompartment 10 is directed perpendicularly to the plane of the drawing,away from the view direction of the observer. The bottom 11 forms theside distal from the radiation. The cover side of the compartment is,conversely, proximal to the radiation.

The electrodes 21-24 are connected with an external alternating currentsource. Between the electrodes, an electrical alternating field isproduced. By means of the external radiation, a heating of one or all ofthe electrodes takes place. For instance, provision can be made thatonly the upper, electrodes, proximal to the radiation are heated.

In accord with a preferred embodiment the provided electrodes on thebottom and cover surfaces are shaped differently, so that, by theprojection in the direction of the radiation the shapes of theelectrodes are not congruent. This enables, upon option, that only thelower electrodes on the compartment bottom, or only the upper electrodeson the compartment top are subjected to radiation. The asymmetry of theelectrodes is illustrated in FIG. 2. The lower electrodes 21 22 possessa greater length, so that they extend themselves beyond the projectionof the upper electrodes 23, 24.

Upon focusing the external radiation onto the ends of the lowerelectrodes 21, 22 (reference number 40), then only the lower electrodesare heated.

By means of the heating, an inhomogeneity takes place in the liquidflowing through the compartment 10. Due to the action of the electric,alternating field, there occurs in the liquid zone, which is stressed bythe electrodes and the radiation absorber, a convective turnover of theliquids, so that these are mixed.

In FIG. 3, another embodiment of the invention is illustrated inschematic top view, wherein the microsystem 100 exhibits two convergingchannels 15, 16. In this embodiment, the electrode arrangement 20 isformed by an 8-pole assembly. Four electrodes 21-24 (shown with greaterdiameters) are to be found on the bottom of the compartment 10. Theremaining four electrodes 25-28 are arranged on the top cover surface(not shown). The 8-pole electrode assembly generates, when a rotationalvoltage is applied thereto, a field cage, in which, in a known manner, aparticle, such as a biological cell, can be maintained in a state ofsuspension.

The purpose of the arrangement illustrated in FIG. 3 is to be found, inthat the particle 50 is to be treated simultaneously with the liquidsflowing out of the converging channels 15, 16. The electrode arrangement20, is simultaneously used first for the establishment of the dielectricfield cage and second for the generation of the electrical alternatingfield to bring about the convective liquid movement. Since, analogous tothe presentation in FIG. 2, the lower and the upper electrodes in thedirection of the radiation are not congruent, the lower electrodes atthe point 40 can be subjected to targeted external focusing and therebyheated. The inflowing liquids are made turbulent in the zone of thefield cage.

Deviating from the presented embodiment example, an intermixing of theliquid can also be achieved with a planar electrode arrangement, whichonly includes voltage impressed electrodes 21-24 on the bottom surface,while on the side proximal to the radiation no electrodes, or free(floating) electrodes are provided. However, by this means, anintermixing is carried out with only small effectivity.

The disclosed features in the foregoing description in their variousconfigurations, in the drawings, and in the claims can be of consequencein realizing the invention, not only individually, but also in optionalcombinations.

1. A method for generating convective motion in a liquid in a fluidicmicrosystem, said method comprising: providing the liquid in at leastone compartment of the microsystem; applying a time-variant voltage toan electrode arrangement to provide a corresponding time-variantelectrical field in the liquid; providing a thermal gradient in theliquid simultaneously with providing the electrical field in the liquid,wherein the thermal gradient is provided by at least one radiationabsorber located in the at least one compartment being locallyirradiated by at least one external radiation field formed by a singlefocus laser or a multifocus laser, wherein a wavelength of the laser isselected in a wavelength range in which the liquid and a suspendedparticulate in the liquid have no absorption, or possess only anabsorption which is negligible in comparison to an absorption of the atleast one radiation absorber.
 2. The method of claim 1, wherein the atleast one radiation absorber is formed by an absorber surface on a wallof the compartment, by an electrode of the electrode arrangement or by aradiation absorbing surface pattern on an electrode of the electrodearrangement.
 3. The method of claim 1, wherein the laser emits infraredradiation, with which the at least one radiation absorber is inductivelyheated.
 4. The method of claim 1, wherein the at least one externalradiation field is coupled through a transparent wall of the compartmentor is coupled by a light transmitting optical fiber.
 5. The method ofclaim 1, wherein, for the establishment of the thermal gradient, aplurality of radiation absorbers in the compartment are irradiatedsimultaneously or alternately.
 6. The method of claim 1, wherein thetime related changing of the electrical field is produced by applying tothe electrode arrangement an alternating current having a frequency ofat least 1 kHz.
 7. The method of claim 6, wherein the electrodearrangement is subjected to alternating voltage having a frequencycorresponding to an average, inverse dielectric relaxation time of theliquid.
 8. The method of claim 1, wherein a plurality of radiationabsorbers are irradiated in a cascade manner in a channel of themicrosystem.
 9. The method of claim 1, wherein electrodes of theelectrode arrangement are subjected to voltage to simultaneouslygenerate the time-variant electrical fields and for pulsating fields fordielectric manipulation of particles suspended in the liquid.
 10. Afluidic microsystem comprising: at least one compartment for acceptanceand/or throughput of a liquid, an electrode arrangement in the at leastone compartment and designed for generating time-variant electric fieldsin the at least one compartment, at least one affixed radiation absorberin the at least one compartment, and forming a defined spatialdelineation of at least one radiation absorbing zone, and a single focuslaser or a multifocus laser adapted to irradiate the at least oneradiation absorber, wherein a wavelength of the laser is in a wavelengthrange in which the liquid and a suspended particulate in the liquid haveno absorption, or possess only an absorption which is negligible incomparison to an absorption of the at least one radiation absorber. 11.The microsystem of claim 10, wherein the at least one radiation absorberis formed by at least one absorber surface on a wall of the compartment,or by an electrode of the electrode arrangement or by a radiationabsorbing surface pattern on at least one electrode.
 12. The microsystemof claim 10, wherein the radiation absorbing area is respectively formedfrom an infrared absorbing material.
 13. The micro system of claim 12,wherein the radiation absorbing material comprises at least one oftitanium, platinum, tantalum and silicon.
 14. The microsystem of claim10, wherein at least one wall of the compartment is constructed of atransparent material.
 15. The microsystem of claim 10, wherein at leastone electrode comprises a transparent, electrical conducting material.16. The microsystem of claim 10, wherein electrodes of the electrodearrangement in the at least one compartment are spatially displaced, sothat direct radiation targeting the electrodes is made possible for anexternal source of radiation.